Cell signaling pathways play an important role in cell growth, proliferation and differentiation. In normal cell growth, growth factors, through receptor activation (e.g. PDGF or EGF), activate MAP kinase pathways. The Ras/Raf kinase pathway is one of the most important and most well understood MAP kinase pathways involved in normal and uncontrolled cell growth. Active GTP-bound Ras leads to the activation of a cascade of serine/threonine kinases. One of the several groups of kinases known to require GTP-bound Ras for their activation is the Raf family. Upon activation Raf phosphorylates “mitogen-activated ERK activating kinases” (MEK)-1 and MEK2.
Some cancers contain mutations which result in the continuous activation of this pathway due to continuous production of growth factors. Other mutations can lead to defects in the deactivation of the activated GTP-bound Ras complex, again resulting in activation of the MAP kinase pathway. Mutated, oncogenic forms of Ras are found in 50% of colon and >90% pancreatic cancers as well as many others types of cancers. Recently, bRaf mutations have been identified in more than 60% of malignant melanoma.
These mutations in bRaf result in a constitutively active MAP kinase cascade. Studies of primary tumor samples and cell lines have also shown constitutive or over activation of the MAP kinase pathway in cancers of pancreas, colon, lung, ovary and kidney. Hence, there is a strong correlation between cancers and an overactive MAP kinase pathway resulting from genetic mutations.
As constitutive or over activation of MAP kinase cascade plays a pivotal role in cell proliferation and differentiation, inhibition of this pathway is believed to be beneficial in hyperproliferative diseases. MEK is a key player in this pathway as it is downstream of Ras and Raf. Additionally, it is an attractive therapeutic target because the only known substrates for MEK phosphorylation are the MAP kinases, ERK1 and 2.
Inhibition of MEK has been shown to have potential therapeutic benefit in several studies. For example, small molecule MEK inhibitors have been shown to inhibit human tumor growth in nude mouse xenografts, block static allodynia in animals and inhibit growth of acute myeloid leukemia cells.
Thus, MEK1 and MEK2 are validated and accepted targets for anti-proliferative therapies, even when the oncogenic mutation does not affect MEK structure or expression.
The MEK cascade has also been implicated in inflammatory diseases and disorders. This includes both acute and chronic inflammation disorders. Examples of such disorders are allergic contact dermatitis, rheumatoid arthritis, osteoarthritis, inflammatory bowel diseases, chronic obstructive pulmonary disorder, psoriasis, multiple sclerosis, asthma, diseases and disorders related to diabetic complications, and inflammatory complications of the cardiovascular system such as acute coronary syndrome. Among inflammatory bowel diseases are Crohn's disease and ulcerative colitis.